Microfluidic Devices for Angiogenesis - Mechanical and Chemical Signaling in Angiogenesis - page 109

the literature, in large part due to the newly developed capabilities of microfluidic
systems, and many questions regarding mechanisms of action remain to be answered.

5 Heterotypic Cell Culture in Microfluidics

5.1 The Importance of Co-Culture in Angiogenesis

A number of recent studies have begun to use microfluidics to examine interac-
tions between multiple cell types, and some have specifically examined interac-
tions in the context of angiogenesis. There exists a strong motivation for studies of
this type. Clearly, in an attempt to replicate true physiology, many types of
cell-cell interactions need to be replicated, and the addition of other, non-endo-
thelial cell types helps in that regard. Whether the objective is to create an engi-
neered organ or to screen for new drugs, the more closely one can mimic in vivo
conditions, the better. At the same time, however, the addition of other cell types
greatly complicates the process of understanding all of the relevant communication
pathways. In order to provide some added realism while avoiding the over-
whelming complexity of the in vivo situation, investigators have typically intro-
duced only one or two accessory cell types; cells that communicate with ECs in a
way that influences the particular behavior of interest.

5.2 Experiments with Multiple Cell Types

One example of this has been the co-culture of endothelial cells with tumor cells,
either as isolated cells [ 90 ] or as tumor spheroids. Experiments of this type have
demonstrated that, depending upon the tumor cell type, the nature of the inter-
action can be very different, giving rise to different forms of invasion, or producing
various levels of stimulation of the EC monolayer (Fig. 6 a). In either case, one
objective has been to study the role of endothelial-secreted factors that might act as
chemoattractants to cancer cells, as a stimulus drawing the cells to the vascular or
lymphatic system where they might intravasate and be transported to another
location where they could initiate a metastatic tumor. Cells have been introduced
both suspended in matrix material [ 100 ] (Fig. 6 c) or plated onto the surface of a
separate channel [ 101 ], and induced to migrate preferentially toward the endo-
thelial cells.
Of greater relevance to this chapter, factors secreted by tumor cells have
induced sprouting angiogenesis. In a series of preliminary studies using a micro-
fluidic platform consisting of 2 or 3 media channels and 1 or 2 gel regions, the role
of various cell types on endothelial invasion into gel has been investigated (e.g.,
[ 102 ]).

Interestingly, the effects of different cancer cell lines have shown